1,3,5-Triazine derivatives as ligands for human adenosine-A3 receptors

ABSTRACT

The invention relates to a group of novel triazine derivatives which are ligands for human adenosine-A 3  receptors, as well as to pharmaceutical compositions containing a pharmacologically active amount of at least one of these compounds as an active ingredient. The invention relates to compounds of the general formula (1)  
                 
 
     wherein Y represents a group of the general formula (A), (B) or (C)  
                 
 
     and all other symbols have the meanings as given in the description.

[0001] This application claims priority to European Patent Application Number 02077310.7, filed May 30, 2002 and The Netherlands Patent Application Number NL 1020725, filed May 30, 2002, the contents of which are incorporated herein by reference.

[0002] The present invention relates to a group of novel triazine derivatives which are ligands for human adenosine-A₃ receptors. The invention also relates to pharmaceutical compositions containing a pharmacologically active amount of at least one of these novel triazine derivatives as an active ingredient.

[0003] Caffeine and theophylline, two well known natural compounds, exert their pharmacological activities by interacting with adenosine receptors. This discovery had a major impact on adenosine receptor research. At present, four types of adenosine receptors have been identified and designated A₁, A_(2A), A_(2B) and A₃ respectively. All four belong to the super-family of seven transmembrane G-protein coupled receptors. Adenosine receptors are ubiquitous and involved in a great variety of biological processes. Thus, during the past decades the therapeutic potential of adenosine receptor ligands has resulted in a substantial research interest. Recent reviews are: S. Hess, Recent advances in adenosine receptor antagonist research, Expert Opin. Ther. Patents, 11, 1547-1562, 2001, and M. A. Jacobson, Adenosine receptor agonists, Expert Opin. Ther. Patents, 12(4), 489-501, 2002.

[0004] Ligands for the various adenosine receptors are the subject of a large number of patent applications and patents. In only two of those triazines are described. WO 991163 describes a series of 2,4-bisphenyl substituted triazines showing nanomolar affinity for human adenosine-A₁ receptors.

[0005] The second patent application describing triazines, JP 11158073, describes a series of substituted 1,3,5-triazines which are ligands for human adenosine-A₃ receptors, the most potent of which having affinities around 15 nM.

[0006] Surprisingly, it has now been found that in a series of triazine derivatives with novel combinations of substituents, a group of compounds was shown to have an affinity for human adenosine-A₃ receptors in the low nanomolar range.

[0007] The invention relates to compounds of the general formula (1)

[0008] wherein:

[0009] R₁ represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF₃, NH₂, N-(di)-alkyl(1-3C), N-(di)-alkenyl(1-3C), N-(di)-alkynyl(1-3C), N-alkyl(1-3C)alkenyl(1-3C), N-alkyl(1-3C)alkynyl(1-3C), N-alkenyl(1-3C)alkynyl(1-3C) or an optionally substituted C₂-C₈ cycloalkylamino group,

[0010] R₂, R₃ and R₄ independently represent H, halogen, alkyl(1-3C), CF₃, OH, O-alkyl(1-3C), phenoxy, hydroxyalkyl(1-3C), alkoxy(1-2C)-alkyl(1-2C), phenyl, N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF₃, SCH₃, SOCH₃, SO₂CH₃ or R₂ and R₃ together with the phenyl ring to which they are attached, represent an optionally substituted benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene ring system,

[0011] X represents NH, N-alkyl(1-3C), CH₂, O, S or a carbon-carbon bond,

[0012] Y represents a group of the general formula (A), (B) or (C):

[0013] in which:

[0014] R₅ is either OH or CH₂OH

[0015] R₆ represents H, alkyl(1-3C), phenyl, NH₂, N-(di)-alkyl(1-3C), OH, O-alkyl(1-3C) or hydroxyalkyl(1-2C);

[0016] n has the value of 0, 1 or 2;

[0017] R₇ represents alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C),

[0018] R₈ and R₉ independently represent H, halogen, alkyl(1-3C), CF₃, OH, O-alkyl(1-3C), N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF₃, SCH₃, SOCH₃, or SO₂CH₃,

[0019] R₁₀ represents H or alkyl(1-3C),

[0020] R₁₁ represents H, alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C),

[0021] Z represents NOH, NOalkyl(1-3C), O or S,

[0022] and pharmacologically acceptable salts thereof.

[0023] In the description of the substituents the abbreviation ‘alkyl(1-3C)’ means ‘methyl, ethyl, n-propyl or isopropyl’.

[0024] In this specification ‘C₂-C₈ cycloalkylamino’ means any cyclic amine containing from 2 to 8 carbons in the ring. The cycloalkylamino ring may contain other atoms and may be optionally substituted. Examples of C₂-C₈ cycloalkylamino include pyrrolidinyl, piperidinyl, morpholinyl, aziridinyl, pyrrolinyl and the like.

[0025] In this specification ‘optionally substituted’ means that a group may or may not be further substituted by one or more groups selected from alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxyl, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, oxo, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6-membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulphur. Optional substituents may themselves bear additional optional substituents. Preferred optional substituents include C₁₋₃ alkyl such as for example methyl, ethyl, and trifluoromethyl, fluoro, chloro, bromo, hydroxyl, C₁₋₃ alkyloxy such as for example methoxy, ethoxy and trifluoromethoxy, and amino.

[0026] All compounds having formula (1) in which the substituents on asymmetrical carbon atoms are in either the R-configuration or the S-configuration belong to the invention.

[0027] Also prodrugs, i.e. compounds which when administered to humans by any known route, are metabolized to compounds having formula (1), belong to the invention. In particular this relates to compounds with primary or secondary amino groups or hydroxy groups, a typical example being the compound with formula (9) and its enantiomers (see below). Such compounds can be reacted with organic acids to yield compounds which can be metabolized to compounds having formula (1).

[0028] The invention particularly relates to compounds having formula (1) wherein R₁ represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF₃, NH₂ or N-(di)-alkyl(1-3C), and all other symbols have the meanings as given above.

[0029] More particular the invention relates to compounds having formula (1) wherein R₁=Cl, R₂=H, X=NH, Y is either group (A), (B) or (C), R₆=H, n=1, Z=O, R₁₀=H and R₃, R₄, R₅, R₇, R₈, R₉ and R₁₁ have the meanings as described above, and including all possible stereo-isomers and prodrugs as outlined above, thus as represented by the general formulas (2), (3) and (4):

[0030] Yet more particular the invention relates to compounds of either formula (2), (3) or (4) in which R₅=3−CH₂OH; R₇=CH₃; R₈=H; R₉=H; R₁₁=CH₃ and R₃ and R₄ have the meanings as described above, and including all possible stereo-isomers and prodrugs as outlined above, thus as represented by the general formulas (5), (6) and (7):

[0031] Even more preferred is the compound having formula (8) and its enantiomers.

[0032] The best mode of the invention is the compound represented by formula (9):

[0033] This compound has an affinity for human adenosine-A₃ receptors of pK_(i)9.0±0.3.

[0034] The compounds of the invention and their salts can be obtained according to the general routes outlined below. Those with R₁=Cl are synthesized according to scheme 1:

[0035] Experimental details for the first step in this general route are given in:

[0036] J. Amer. Chem. Soc. 116, 1994, 4326 for X=NH;

[0037] Chem. Pharm. Bull. 45, 1997, 291 for X=N-alkyl;

[0038] Tetrahedron 56, 2000, 9705 for X=CH₂;

[0039] Pol. J. Chem. 74, 2000, 837 for X=0;

[0040] J Chem. Soc. C 1967, 466 for X=S, and in

[0041] Tetrahedron 56, 2000, 9705 for X=carbon-carbon bond.

[0042] The disclosure of these documents is specifically incorporated herein by reference.

[0043] The compounds of the invention with R₁=F or Br can be obtained fully analogously from the corresponding tri-halo derivatives. Experimental details are given in:

[0044] J. Med Chem. 36 (26), 4195-4200, 1993 for R₁ is F, and in

[0045] J. Prakt. Chem. 82, 536, 1910 for R₁=Br.

[0046] The disclosure of these documents is specifically incorporated herein by reference.

[0047] The compounds of the invention with R₁=O-alkyl(1-3C) or any of the amine substituents: NH₂, N-(di)-alkyl(1-3C), N-(di)-alkenyl(1-3C), N-(di)-alkynyl(1-3C), N-alkyl(1-3C)alkenyl(1-3C), N-alkyl(1-3C) alkynyl(1-3C), N-alkenyl(1-3C)alkynyl(1-3C) or an optionally substituted C₂-C₈ cycloalkylamino group, can be obtained by further substitution of the chloro-derivatives as outlined below in scheme 2:

[0048] Experimental details are given in:

[0049] Heterocycles 31 (5), 895-909, 1990 for R₁=alkoxy, and in

[0050] Tetrahedron, 54 (1998) 4051-4065 for R₁=(substituted) amine.

[0051] The disclosure of these documents is specifically incorporated herein by reference.

[0052] Compounds of the invention with R₁=alkyl(1-3C), CF₃ or iodine can be obtained by following the sequence of synthetic steps outlined below in Scheme 3.

[0053] Experimental details are given in:

[0054] J. Med Chem 42 (5), 805-818, 1999 for R₁=alkyl,

[0055] J. Chem Soc., Chem Comm 1988, (10) 638-639 for R₁=CF₃, and in

[0056] Eur. J. Org. Chem., 2002, 4181-4184 for R₁=iodine

[0057] The disclosure of these documents is specifically incorporated herein by reference.

[0058] Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid.

[0059] Suitable acid addition salts can be formed with inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid and nitric acid, or with organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, trifluoro acetic acid, benzoic acid, p-toluene sulphonic acid, methanesulphonic acid and naphthalene sulphonic acid.

[0060] The compounds of the invention of the general formula (1), as well as the salts thereof, have adenosine-A₃ (ant)agonistic activity. They are useful in the treatment of disorders in which adenosine-A₃ receptors are involved, or that can be treated via manipulation of those receptors. For instance in: acute and chronic pain, inflammatory diseases including, arthritis, multiple sclerosis, asthma and psoriasis; gastro-intestinal disorders such as ulcers, inflammatory bowel disease (Crohn's disease) and ulcerative colitis; allergic responses such as eczema, atopic dermatitis and rhinitis; cardio-vascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological disorders like glaucoma; respiratory disorders including chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; central nervous system disorders including various forms of epilepsy, stroke, depression, sleep apnoea; disorders characterized by impairment of cognition and memory such as Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease, neurorehabilitation (post-traumatic brain lesions); acute brain or spinal cord injury; diabetes, osteoporosis, diseases of the immune system, various carcinomas and leukemia, bacterial and viral infections.

[0061] The adenosine-A₃ receptor (ant)agonistic properties of the compounds of the invention were determined using the method outlined below.

Receptor Binding to Human Adenosine-A₃ Receptors

[0062] Affinity of the compounds for human adenosine-A₃ receptors was determined using the receptor binding assay described by C. A. Salvatore et al.: Molecular cloning and characterization of the human A₃ adenosine receptor, Proc. Natl. Acad. Sci. USA, 90, 10365-10369, 1993. Briefly, membrane preparations were obtained from human recombinant (HEK 293) cells in which the human adenosine-A₃ receptor was stably expressed. Membranes were incubated at 22° C. for 90 minutes with [¹²⁵l]-AB-MECA in the absence or presence of testcompounds in a concentration range from 10 μM down to 0.1 nM, diluted in a suitable buffer. Separation of bound radioactivity from free was done by filtration through Packard GF/B glass fiber filters with several washings with ice-cold buffer using a Packard cell harvester. Bound radioactivity was measured with a scintillation counter (Topcount, Packard) using a liquid scintillation cocktail (Microscint 0, Packard). Measured radioactivity was plotted against the concentration of the displacing test compound and displacement curves were calculated by four-parameter logistic regression, resulting in IC₅₀ values, i.e. that concentration of displacing compound by which 50% of the radioligand is displaced. Affinity pK₁ values were calculated by correcting the IC₅₀ values for radioligand concentration and its affinity for the human adenosine-A₃ receptor according to the Cheng-Prusoff equation:

pK _(l)=−log (IC ₅₀/(1+S/K _(d)))

[0063] in which the IC₅₀ is as described above, S is the concentration [¹²⁵l]-AB-MECA used in the assay expressed in mol/l (typically 0.1 nM), and K_(d) is the equilibrium dissociation constant of [¹²⁵l]-AB-MECA for human adenosine-A₃ receptors (0.22 nM).

[0064] The compounds of the invention have a high affinity for adenosine-A₃ receptors in the binding assay described above. This property makes them useful in the treatment of disorders in which adenosine-A₃ receptors are involved, or that can be treated via manipulation of these receptors.

EXAMPLES (1S,2R)-2-{[4-chloro-6-(3,4-methylenedioxy-phenylamino)-[1,3,5]triazin-2-yl]-amino}-1-phenyl-propan-1-ol

[0065] To a solution of cyanuric chloride (1.84 gr) in acetonitrile (20 ml), kept at a temperature of −20° C. under stirring, dropwise were subsequently added solutions of 3,4-methylenedioxy-aniline (1.37 gr) in acetonitrile (20 ml) and diisopropylethylamine (DIPEA) (1.29 gr) in acetonitrile (20 ml). After stirring at −20° C. for 1 hour, again dropwise were subsequently added solutions of DIPEA (1.29 gr) in acetonitrile (20 ml) and (1 S,2R)-(+)-norephedrine (1.51 gr) in acetonitrile (20 ml). The mixture was allowed to warm to room temperature and was stirred for another 2 hours. The resulting reaction mixture was concentrated in vacuo. After addition of ethylacetate (250 ml) the organic layer was subsequently washed with a solution of HCl in water (1M, 100 ml) , a solution of NaOH in water (1 M, 100 ml) and brine (50 ml). The organic layer was dried over sodiumsulphate, filtered and concentrated in vacuo. The resulting product was purified by column chromatography using silicagel and a mixture of heptane: ethylacetate (3:1) as the eluent. The resulting pure product (formula (9), see above, example B-44, see table) was obtained as a white solid in 80% yield.

[0066] The invention is further illustrated by means of the following specific examples listed in the tables below and represented by the general formula:

[0067] wherein Y represents a group of the general formula (A), (B) or (C):

[0068] These examples are only intended to further illustrate the invention in more detail, and therefore are not deemed to restrict the scope of the invention in any way. nr R₁ X R₂ R₃ R₄ Y n R₅ R₆ A-1  Cl NH H H H (A) 1 3-CH₂OH H A-2  Cl NH OCH₃ H H (A) 1 3-CH₂OH H A-3  Cl NH OCH₃ H H (A) 1 3-CH₂OH 4-CH₃ A-4  Cl NH OCH₃ H H (A) 1 3-CH₂OH 4-phenyl A-5  Cl NH OCH₃ H H (A) 1 3-CH₂OH 4-N(CH₃)₂ A-6  Cl NH OCH₃ H H (A) 1 3-CH₂OH 5-CH₂OH A-7  Cl NH H OCH₃ H (A) 1 3-CH₂OH H A-8  Cl NH CH₃ H H (A) 1 3-CH₂OH H A-9  Cl NH Cl H H (A) 1 3-CH₂OH H A-10 Cl NH OC₂H₅ H H (A) 1 3-CH₂OH H A-11 Cl NH H OC₂H₅ H (A) 1 3-CH₂OH H A-12 Cl NH CH(OH)CH₃ H H (A) 1 3-CH₂OH H A-13 Cl NH H 1-morpholinyl H (A) 1 3-CH₂OH H A-14 Cl NH CH₃ CH₃ H (A) 1 3-CH₂OH H A-15 Cl NH F CH₃ H (A) 1 3-CH₂OH H A-16 Cl NH F OCH₃ H (A) 1 3-CH₂OH H A-17 Cl NH OCH₃ H CF₃ (A) 1 3-CH₂OH H A-18 Cl NH OCH₃ H OCH₃ (A) 1 3-CH₂OH H A-19 Cl NH phenyl H (A) 1 3-CH₂OH H A-20 Cl NH —O—CH₂—O— H (A) 1 3-OH H A-21 Cl NH —O—CH₂—O— H (A) 1 4-OH H A-22 Cl NH —O—CH₂—O— H (A) 1 4-OH 4-phenyl A-23 Cl NH H H H (A) 1 4-OH H A-24 Cl NH H CH₃ H (A) 1 4-OH H A-25 Cl NH Cl H H (A) 1 4-OH H A-26 Cl NH OCH₃ H H (A) 1 4-OH H A-27 Cl NH H OCH₃ H (A) 1 4-OH H A-28 Cl NH OC₂H₅ H H (A) 1 4-OH H A-29 Cl NH H OC₂H₅ H (A) 1 4-OH H A-30 Cl NH H (CH₂)₂OH H (A) 1 4-OH H A-31 Cl NH O—phenyl H H (A) 1 4-OH H A-32 Cl NH H O—phenyl H (A) 1 4-OH H A-33 Cl NH H 1-morpholinyl H (A) 1 4-OH H A-34 Cl NH CH₃ CH₃ H (A) 1 4-OH H A-35 Cl NH F CH₃ H (A) 1 4-OH H A-36 Cl NH F OCH₃ H (A) 1 4-OH H A-37 Cl NH OCH₃ H CF₃ (A) 1 4-OH H A-38 Cl NH OCH₃ H OCH₃ (A) 1 4-OH H A-39 Cl NH phenyl H (A) 1 4-OH H A-40 Cl NH O—CH₂—O— H (A) 1 2-CH₂OH H A-41 Cl NH OCH₃ H H (A) 1 2-CH₂OH H A-42 Cl NH H OCH₃ H (A) 1 2-CH₂OH H A-43 Cl NH H OC₂H₅ H (A) 1 2-CH₂OH H A-44 Cl NH H 1-morpholinyl H (A) 1 2-CH₂OH H A-45 Cl NH CH₃ CH₃ H (A) 1 2-CH₂OH H A-46 Cl NH F OCH₃ H (A) 1 2-CH₂OH H A-47 Cl NH OCH₃ H OCH₃ (A) 1 2-CH₂OH H A-48 Cl NH —O—CH₂—O— H (A) 1 3-CH₂OH H A-49 CH₃ NH —O—CH₂—O— H (A) 1 3-CH₂OH H A-50 OCH₃ NH —O—CH₂—O— H (A) 1 3-CH₂OH H A-51 1-morpholinyl NH —O—CH₂—O— H (A) 1 3-CH₂OH H A-52 1-pyrrolidinyl NH —O—CH₂—O— H (A) 1 3-CH₂OH H A-53 NH-propargyl NH —O—CH₂—O— H (A) 1 3-CH₂OH H A-54 Cl NCH₃ —O—CH₂—O— H (A) 1 3-CH₂OH H A-55 Cl O —O—CH₂—O— H (A) 1 3-CH₂OH H A-56 Cl S —O—CH₂—O— H (A) 1 3-CH₂OH H A-57 Cl CH₂ —O—CH₂—O— H (A) 1 3-CH₂OH H A-58 Cl bond —O—CH₂—O— H (A) 1 3-CH₂OH H A-59 Cl NH —O—CH₂—O— H (A) 1 4-CH₂OH H A-60 Cl NH —O—CH₂—O— H (A) 0 3-OH H A-61 Cl NH CH₃ H H (A) 0 3-OH H A-62 Cl NH Cl H H (A) 0 3-OH H A-63 Cl NH OCH₃ H H (A) 0 3-OH H A-64 Cl NH H OCH₃ H (A) 0 3-OH H A-65 Cl NH H OC₂H₅ H (A) 0 3-OH H A-66 Cl NH H 1-morpholinyl H (A) 0 3-OH H A-68 Cl NH CH₃ CH₃ H (A) 0 3-OH H A-69 Cl NH F OCH₃ H (A) 0 3-OH H A-70 Cl NH phenyl H (A) 0 3-OH H A-71 Cl NH —O—CH₂—O— H (A) 0 3-CH₂OH H nr R₁ X R₂ R₃ R₄ Y R₇ R₈ R₉ R₁₀ stereo B-1  Cl NH H H H (B) CH₃ H H H 1S,2R B-2  Cl NH H H H (B) CH₃ H H H 1R,2S B-3  Cl NCH₃ H H H (B) CH₃ H H H 1S,2R B-4  Cl O H H H (B) CH₃ H H H 1S,2R B-5  Cl CH₂ H H H (B) CH₃ H H H 1S,2R B-6  Cl S H H H (B) CH₃ H H H 1S,2R B-7  Cl bond H H H (B) CH₃ H H H 1S,2R B-8  Cl NH H H H (B) CH₃ H H CH₃ 1R,2R B-9  Cl NH OCH₃ H H (B) CH₃ H H H 1S,2R B-10 Cl NH OCH₃ H H (B) CH₃ H H H 1R,2S B-11 Cl NH OCH₃ H H (B) CH₃ H H CH₃ 1R,2R B-12 Cl NH OCH₃ H H (B) CH₂CH₃ H H H 1S,2R B-13 Cl NH OCH₃ H H (B) (CH₂)₂CH₃ H H H 1S,2R B-14 Cl NH OCH₃ H H (B) CH₂-phenyl H H H 1S,2R B-15 Cl NH OCH₃ H H (B) CH₂OH H H H 1S,2R B-16 Cl NH OCH₂CH₃ H H (B) CH₃ H H H 1S,2R B-17 Cl NH OCH₂CH₃ H H (B) CH₃ H H CH₃ 1R,2R B-18 Cl NH CH₃ H H (B) CH₃ H H H 1S,2R B-19 Cl NH Cl H H (B) CH₃ H H H 1S,2R B-20 Cl NH Cl H H (B) CH₃ H H CH₃ 1R,2R B-21 Cl NH CH(OH)CH₃ H H (B) CH₃ H H H 1S,2R B-22 Cl NH CH(OH)CH₃ H H (B) CH₃ H H CH₃ 1R,2R B-23 Cl NH O-phenyy H H (B) CH₃ H H H 1S,2R B-24 Cl NH O—phenyl H H (B) CH₃ H H CH₃ 1R,2R B-25 Cl NH H OCH₃ H (B) CH₃ H H H 1S,2R B-26 Cl NH H OCH₃ H (B) CH₃ H H H 1R,2S B-27 Cl NH H OCH₃ H (B) CH₃ H H CH₃ 1R,2R B-28 Cl NH H OCH₂CH₃ H (B) CH₃ H H H 1S,2R B-29 Cl NH H 1-morpholinyl H (B) CH₃ H H H 1S,2R B-30 Cl NH H CH₃ H (B) CH₃ H H H 1S,2R B-31 Cl NH H CF₃ H (B) CH₃ H H H 1S,2R B-32 Cl NH H O—phenyl H (B) CH₃ H H H 1S,2R B-33 Cl NH H O—phenyl H (B) CH₃ H H CH₃ 1R,2R B-34 Cl NH H (CH₂)₂OH H (B) CH₃ H H CH₃ 1R,2R B-35 Cl NH F CH₃ H (B) CH₃ H H H 1S,2R B-36 Cl NH F OCH₃ H (B) CH₃ H H H 1S,2R B-37 Cl NH F OCH₃ H (B) CH₃ H H CH₃ 1R,2R B-38 Cl NH F OCH₃ H (B) CH₃ H H CH₃ 1R,2S B-39 Cl NH OCH₃ H CF₃ (B) CH₃ H H H 1S,2R B-40 Cl NH OCH₃ H OCH₃ (B) CH₃ H H H 1S,2R B-41 Cl NH OCH₃ H OCH₃ (B) CH₃ H H CH₃ 1R,2R B-42 Cl NH CH₃ CH₃ H (B) CH₃ H H H 1S,2R B-43 Cl NH phenyl H (B) CH₃ H H H 1S,2R B-44 Cl NH —O—CH₂—O— H (B) CH₃ H H H 1S,2R B-45 Cl NH —O—CH₂—O— H (B) CH₃ H H H 1R,2S B-46 Cl NH —O—CH₂—O— H (B) CH₃ H H CH₃ 1S,2R B-47 Cl NH —O—CH₂—O— H (B) CH₃ H H CH₃ 1S,2S B-48 Cl NH —O—CH₂—O— H (B) CH₃ H H CH₃ 1R,2S B-49 Cl NH —O—CH₂—O— H (B) CH₃ H H CH₃ 1R,2R B-50 Cl NCH₃ —O—CH₂—O— H (B) CH₃ H H H 1S,2R B-51 Cl O —O—CH₂—O— H (B) CH₃ H H H 1S,2R B-52 Cl S —O—CH₂—O— H (B) CH₃ H H H 1S,2R B-53 Cl CH₂ —O—CH₂—O— H (B) CH₃ H H H 1S,2R B-54 Cl bond —O—CH₂—O— H (B) CH₃ H H H 1S,2R B-55 Cl NH —O—CH₂—O— H (B) CH₃ 3-OH H H 1R,2S B-56 Cl NH —O—CH₂—O— H (B) CH₃ 4-OH H H 1S,2R B-57 Cl NH —O—CH₂—O— H (B) CH₃ 3-OH 4-OH H 1R,2S B-58 Cl NH —O—CH₂—O— H (B) CH₃ 2-OCH₃ 5-OCH₃ H racemic B-59 NH₂ NH —O—CH₂—O— H (B) CH₃ H H H 1R,2S B-60 N(CH₃)₂ NH —O—CH₂—O— H (B) CH₃ H H H 1R,2S B-61 1-pyrrolidinyl NH —O—CH₂—O— H (B) CH₃ H H H 1S,2R B-62 1-morpholinyl NH —O—CH₂—O— H (B) CH₃ H H H 1S,2R B-63 1-piperidinyl NH —O—CH₂—O— H (B) CH₃ H H H 1S,2R B-64 NH-propargyl NH —O—CH₂—O— H (B) CH₃ H H H 1S,2R B-65 N(CH₃) NH —O—CH₂—O— H (B) CH₃ H H H 1S,2R propargyl B-66 CH₃ NH —O—CH₂—O— H (B) CH₃ H H H 1S,2R B-67 OCH₃ NH —O—CH₂—O— H (B) CH₃ H H H 1S,2R Nr R₁ X R₂ R₃ R₄ Y R₈ R₉ R₁₀ R₁₁ Z C-1  Cl NH —O—CH₂O— H (C) H H H H O C-2  Cl NH —O—CH₂O— H (C) H H H CH₃ O C-3  CH₃ NH —O—CH₂O— H (C) H H H CH₃ O C-4  OCH₃ NH —O—CH₂O— H (C) H H H CH₃ O C-5  Cl NH OCH₃ H H (C) H H H CH₃ O C-6  Cl NH H OCH₃ H (C) H H H CH₃ O C-7  Cl NH —O—CH₂O— H (C) H H H CH₃ N—OH C-8  Cl NH —O—CH₂O— H (C) H H H CH₃ N—OCH₃ C-9  Cl NH —O—CH₂O— H (C) H H H H N—OH C-10 Cl NH OCH₃ H H (C) H H H H N—OH C-11 Cl NH H OCH₃ H (C) H H H H N—OH

EXAMPLES OF PRODRUGS

[0069] To illustrate the concept ‘prodrugs’ the following compounds with the general formula (10) have been prepared: (10)

example R-group Pro-1 propionyl Pro-2 pivaloyl Pro-3 nicotinoyl Pro-4 N-acetyl-isonipecotyl Pro-5 methoxyacetyl Pro-6 acethoxyacetyl Pro-7 nonaoyl

[0070] Prodrugs having formula (10) have no affinity for human adenosine-A3 receptors, but after hydrolysis they generate the compound with formula (9) (see above) which is highly active. 

1. Compounds of the general formula (1)

wherein: R₁ represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF₃, NH₂, N-(di)-alkyl(1-3C), N-(di)-alkenyl(1-3C), N-(di)-alkynyl(1-3C), N-alkyl(1-3C)alkenyl(1-3C), N-alkyl(1-3C)alkynyl(1-3C), N-alkenyl(1-3C)alkynyl(1-3C) or an optionally substituted C₂-C₈ cycloalkylamino group, R₂, R₃and R₄ independently represent H, halogen, alkyl(1-3C), CF₃, OH, O-alkyl(1-3C), phenoxy, hydroxyalkyl(1-3C), alkoxy(1-2C)-alkyl(1-2C), phenyl, N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF₃, SCH₃, SOCH₃, SO₂CH₃ or R₂ and R₃ together with the phenyl ring to which they are attached, represent an optionally substituted benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene ring system, X represents NH, N-alkyl(1-3C), CH₂, O, S or a carbon-carbon bond, Y represents a group of the general formula (A), (B) or (C):

in which: R₅ is either OH or CH₂OH R₆ represents H, alkyl(1-3C), phenyl, NH₂, N-(di)-alkyl(1-3C), OH, O-alkyl(1-3C) or hydroxyalkyl(1-2C); n has the value of 0, 1 or 2; R₇ represents alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C), R₈ and R₉ independently represent H, halogen, alkyl(1-3C), CF₃, OH, O-alkyl(1-3C), N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF₃, SCH₃, SOCH₃, or SO₂CH₃, R₁₀ represents H or alkyl(1-3C), R₁₁ represents H, alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C), Z represents NOH, NOalkyl(1-3C), O or S, pharmacologically acceptable salts thereof, and all compounds having formula (1) in which the substituents on potentially asymmetrical carbon atoms are in either the R-configuration or the S-configuration, as well as prodrugs thereof.
 2. Compounds as claimed in claim 1 of the general formula (1) wherein R₁ represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF₃, NH₂ or N-(di)-alkyl(1-3C); R₂, R₃ and R₄ independently represent H, halogen, alkyl(1-3C), CF₃, OH, O-alkyl(1-3C), phenyl, N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF₃, SCH₃, SOCH₃, SO₂CH₃, or R₂ and R₃ together with the phenyl ring to which they are attached, represent a benzofuran, benzodioxane, or benzodioxolane ring system, X represents NH, N-alkyl(1-3C), CH₂, O, S or a carbon-carbon bond, Y represents a group of the general formula (A) or (B), in which R₅ is either OH or CH₂OH; R₆ represents H, alkyl(1-3C), phenyl, NH₂, N-(di)-alkyl(1-3C), OH, O-alkyl(1-3C) or hydroxyalkyl (1-2C); n has the value of 0, 1 or 2; R₇ represents alkyl(1-3C), benzyl or hydroxyalkyl(1-2C); R₈ and R₉ independently represent H, halogen, alkyl(1-3C), CF₃, OH, O-alkyl(1-3C), N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF₃, SCH₃, SOCH₃, or SO₂CH₃; and R₁₀=H
 3. Compounds as claimed in claim 1 of the general formula (1) wherein Y is a group of the general formula (A) and R₁, R₂, R₃, R₄, R₅, R6, X and n have the meanings as in claim
 1. 4. Compounds as claimed in claim 1 of the general formula (1) wherein Y is a group of the general formula (A) and R₁, R₂, R₃, R₄, R₅, R₆, X and n have the meanings as in claim
 2. 5. Compounds as claimed in claim 1 of the general formula (1) wherein Y is a group of the general formula (B) and R₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₀ and X have the meanings as in claim
 1. 6. Compounds as claimed in claim 1 of the general formula (1) wherein Y is a group of the general formula (B) and R₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₀ and X have the meanings as in claim
 2. 7. Compounds as claimed in claim 1 of the general formula (1) wherein Y is a group of the general formula (C) and R₁, R₂, R₃, R₄, R₈, Rg, R₁₀, R₁₁, X and Z have the meanings as in claim
 1. 8. Compounds as claimed in claim 1 having formula (1) wherein R₁=Cl, R₂=H, X=NH, Y is either group (A), (B) or (C), R₆=H, n=1, Z=O, R₁₀=H and R₃, R₄, R₅, R₇, R₈, R₉ and R₁₁ have the meanings as in claim 1
 9. Compounds as claimed in claim 1 having formula (1) wherein R₁=Cl, R₂=H, X=NH, Y is either group (A), (B) or (C), R₅=3-CH₂OH, R₆=H, n=1, R₇=CH₃; R₈=H; R₉=H, Z=O, R₁₀=H, R₁₁=CH₃ and R₃ and R₄, have the meanings as in claim 1
 10. Compound as claimed in claim 1 having formula (8) and enantiomers thereof:


11. Compound as claimed in claim 1 having formula (9)


12. Pharmaceutical compositions containing a pharmacologically active amount of at least one of the compounds as claimed in one of the claims 1-11 as an active ingredient,
 13. Use of a compound as claimed in one of the claims 1-11 for the preparation of a pharmaceutical composition for the treatment of disorders in which adenosine-A₃ receptors are involved, or that can be treated via manipulation of those receptors,
 14. Use as claimed in claim 13 characterized in that said disorders are acute and chronic pain, inflammatory diseases including, arthritis, multiple sclerosis, asthma and psoriasis; gastrointestinal disorders such as ulcers, inflammatory bowel disease (Crohn's disease) and ulcerative colitis; allergic responses such as eczema, atopic dermatitis and rhinitis; cardiovascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological disorders like glaucoma; respiratory disorders including chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; central nervous system disorders including various forms of epilepsy, stroke, depression, sleep apnoea; disorders characterized by impairment of cognition and memory such as Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease, neurorehabilitation (post-traumatic brain lesions); acute brain or spinal cord injury; diabetes, osteoporosis, diseases of the immune system, various carcinomas and leukemia, bacterial and viral infections. 